Disorder with characteristics of premature aging. Affected persons have thin skin, go bald or gray early, and develop diseases of aging decades earlier than normal individuals. Not all systems are affected; there is no senility, no aging in the central nervous system. There are two major types. In the extremely rare Hutchinson-Gilford syndrome, children look 60 years old by age 10 and die at an average age of 13. The unrelated Werner syndrome is a recessive hereditary disease that begins in young adulthood and makes patients look 30 years older than they are; their average life span is 47 years.
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Hutchinson-Gilford Progeria syndrome is an extremely rare condition in which physical aspects of aging are greatly accelerated, and few affected children live past age 13. About 1 in 8 million babies are born with this condition. It is a genetic condition, but occurs sporadically and is usually not inherited in families.
Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.
Growth hormone treatment has been attempted.
A type of anti-cancer drug, the farnesyltransferase inhibitors (FTIs), have been proposed, but their use has been mostly limited to animal models. A phase II clinical trial using the FTI Lonafarnib began in May 2007.
Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They also do not develop "wear and tear" conditions commonly associated with aging, like cataracts and osteoarthritis.
One study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are 48 known cases in the world.
Approximately 100 cases have been formally identified in medical history.
Classical Hutchinson–Gilford Progeria Syndrome is not passed on from parent to child, because most affected children don't live long enough to have children themselves. It is usually caused by a new (sporadic) mutation during the division of the cells that create unfertilized egg or sperm.
Hutchinson–Gilford Progeria Syndrome is genetically dominant, therefore parents who are healthy cannot pass it on to their children.
However, there are milder cases in which either the gene is not expressed in parents, or a different gene is responsible for a different form of progeria, and healthy parents can pass on their children.
Three families have been identified as having more than one child with the disease. The first was a family in India that has five children with progeria, two of which are now deceased. The eldest daughter with progeria is 19 years old, and their eldest son with progeria is 17, both having survived longer than typical among people with progeria. Their other living child with progeria is 7. The family was a subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children.
In 2006, the Vandersweets, a family in Belgium, who already had one child diagnosed with progeria, were informed that their second child also had the disease.
The third case is a family that lives in Aguacatan in Guatemala. The family consists of 3 children. 1, 7 and 18 years old. The 7 and 18 year old both have been diagnosed with Progeria. Status of the infant is still uncertain.
A 2003 report in Nature said progeria may be a de novo dominant trait. It develops during cell division in a newly conceived child or in the gametes of one of the parents. It is caused by mutations in LMNA (Lamin A protein) gene on chromosome 1; The mutated form of Lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who didn't know anything about progeria, until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.
Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated, and this allows Prelamin A to bind membranes, specifically the nuclear membrane. After Prelamin A has been localized to the cell nuclear membrane the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now Lamin A, is no longer membrane-bound and carries out functions inside the nucleus.
In HGPS the recognition site that the enzyme requires for cleavage of Prelamin A to Lamin A is mutated. Lamin A cannot be produced and Prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing. This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.
A study which compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage and demethylation of histone leading to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin A defects contribute to normal aging.
This method does not directly 'cure' the underlying cause of progeria. This method prevents Prelamin A going to the nucleus in the first place so no Prelamin A can build up on the nuclear membrane, but equally there is no production of normal Lamin A in the nucleus. Luckily Lamin A does not appear to be essential, indeed mouse models in which the genes for Prelamin A and C are knocked out show no symptoms. This also shows that it is the build up of Prelamin A in the wrong place, rather than the loss of the normal function of Lamin A that causes the disease.
It was hypothesized that part of the reason that treatment with an FFI such as alendronate is inefficient due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FFI and statins was tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects".
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